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Cell Rep. 2015 Nov 10;13(6):1103-1109. doi: 10.1016/j.celrep.2015.09.077. Epub 2015 Oct 29.

APOBEC-Induced Cancer Mutations Are Uniquely Enriched in Early-Replicating, Gene-Dense, and Active Chromatin Regions.

Author information

1
Research and Training Center on Bioinformatics, A.A. Kharkevich Institute for Information Transmission Problems, RAS, Moscow 127051, Russia.
2
National Institute of Environmental Health Sciences, Durham, NC 27709, USA; School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA.
3
Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
4
Departments of Genome Sciences and Medicine, University of Washington, Seattle, WA 98195, USA.
5
National Institute of Environmental Health Sciences, Durham, NC 27709, USA.
6
National Institute of Environmental Health Sciences, Durham, NC 27709, USA. Electronic address: gordenin@niehs.nih.gov.
7
Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: ssunyaev@rics.bwh.harvard.edu.

Abstract

An antiviral component of the human innate immune system-the APOBEC cytidine deaminases-was recently identified as a prominent source of mutations in cancers. Here, we investigated the distribution of APOBEC-induced mutations across the genomes of 119 breast and 24 lung cancer samples. While the rate of most mutations is known to be elevated in late-replicating regions that are characterized by reduced chromatin accessibility and low gene density, we observed a marked enrichment of APOBEC mutations in early-replicating regions. This unusual mutagenesis profile may be associated with a higher propensity to form single-strand DNA substrates for APOBEC enzymes in early-replicating regions and should be accounted for in statistical analyses of cancer genome mutation catalogs aimed at understanding the mechanisms of carcinogenesis as well as highlighting genes that are significantly mutated in cancer.

PMID:
26527001
PMCID:
PMC4644490
DOI:
10.1016/j.celrep.2015.09.077
[Indexed for MEDLINE]
Free PMC Article

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